Diagnostic and therapeutic odyssey of two patients with compound heterozygous leptin receptor deficiency

The girl is the second child of German, non-consanguineous parents. She was a newborn of 39 weeks of gestational age, weighted 3690 g, and had a birth length of 54 cm. Already in the first weeks of her life, the girl showed signs of hyperphagia by crying regularly after the end of a meal and only calmed down after further food intake. A perceptible feeling of satiety did not occur even after extensive food intake. Excessive weight gain within the first year of life led to a body weight of 18 kg (BMI 28.1 kg/m², BMI SDS 6.2) (Fig. 1a). Despite numerous diagnostic examinations, no causal diagnosis could be found for the extreme early-onset obesity (Table 1). The persistent desire for food and the continuous weight gain (Fig. 1a) played a major role in daily family life and massively distressed the girl and her family. Negative social experiences at school (e.g. bullying and teasing) led to social isolation. Intensive, interdisciplinary, behavioural treatments to reduce weight were unsuccessful in the long term (Table 2). Repeated setbacks after frustrating weight loss attempts caused a deep depression with suicidal thoughts, but no drug treatment was required. After exhaustion of common therapeutic approaches, she finally decided to undergo bariatric surgery at the age of 18 years. At this time, she weighed 188 kg (BMI 67.7 kg/m²). As a result, she lost 38 kg within 1 year followed by rapid weight regain of 22 kg within 8 months (Fig. 1). However, hypogonadotropic hypogonadism diagnosed at the age of 17 resolved one year after bariatric surgery.

The boy was born with a gestational age of 40 weeks, a birth weight of 3320 g, and a birth length of 50 cm. He is the second child from healthy, non-consanguineous parents of German-Polish origin. Since the first year of life, the boy had permanent hunger, followed by excessive weight gain. Consequently, he weighed 25 kg at the age of 2 years (BMI 33.0 kg/m², BMI SDS 5.5). His extreme body weight restricted his mobility and delayed age-appropriate gross motor development (Fig. 1b). Therefore, comprehensive diagnostics were performed to find the cause of the early-onset obesity. However, no causal diagnosis could be found (Table 1). At the age of 8 years, short stature and growth hormone deficiency were diagnosed. During 3 years of growth hormone treatment, he caught up to a height within normal range from 1.24 to 1.55 m but he also gained weight from 42.5 to 101.5 kg. He attempted a number of conservative treatment approaches to reduce weight without any appreciable success (Table 2). He behaved dissocially and aggressively towards peers and adults, partly in response to negative social experiences, accusations, and teasing. The familiar atmosphere was extremely tense due to his permanent demand for food, his extreme obesity, and the lack of a medical explanation. Finally, he developed a deep depression with suicidal thoughts as a result of the immense physical, mental, familiar, and social stresses. However, he required no drugs to treat depression. At the age of 14 years and a body weight of 154 kg (BMI 55.2 kg/m²), he received gastric banding which helped him to lose 16 kg within one year. In the same year as bariatric surgery, he obtained the diagnosis of hypogonadotropic hypogonadism, which could no longer be detected 4 years after gastric banding. In total, he lost 49 kg within 8 years after gastric banding. This weight reduction seems to be impressive, but it should be noted that the follow-up process after gastric banding was associated with severe complications. Hence, he suffered from recurrent episodes of severe epigastric pains, nausea, vomiting, and diarrhoea. This could also have contributed to the impressive weight reduction. In total, the complications of the gastric banding lead to a deterioration in quality of life. At the age of 25 years, the gastric band had to be removed due to gastric band migration with severe epigastric pains, nausea, and vomiting (Table 2).

At the time of diagnosis, patient 1 is 20 years old, lives on her own, and is completing a training. She weighs 172 kg and has numerous obesity-associated comorbidities (dyslipidaemia, hyperinsulinaemia, hepatic steatosis, hyperuricaemia, and a sleep apnea syndrome). Furthermore, she has a hypochromic microcytic anaemia due to iron deficiency and vitamin D deficiency.

Patient 2 is 29 years old, is unemployed, and lives with his girlfriend in a shared apartment. He is holding a disabled person’s pass with a degree of disability of 60%. He weighs 120.5 kg 4 years after gastric band removal. Apart from obesity, he suffers from bronchial asthma, atopic dermatitis, and episodes of recurrent diarrhoea and vomiting.

Selected clinical and laboratory findings in the two patients are presented in Table 3.

Numerous endocrinological and syndromic diseases known to cause early-onset obesity were excluded in both patients (Tables 1 and 2). Moreover, it seemed inappropriate to attribute the extreme early-onset obesity solely to an unfavourable lifestyle. Based on recent findings on monogenetic causes of obesity, molecular genetic examinations were initiated. For molecular genetic diagnostic, the genomic DNA of both patients was isolated from leucocytes. Subsequently, the DNA was amplified by polymerase chain reaction for all coding exons from the leptin receptor (LEPR) gene and then sequenced by Sanger method. The available sequence data were compared with the common LEPR reference sequence (NM_002303.4). The results show that compound heterozygous variants in the LEPR gene are the cause for the severe early-onset obesity in both patients. Patient 1 has a splice site/frameshift deletion (c.2598-3_2607delTAGAATGAAAAAG) as well as a missense mutation (c.2227 T>C [p.Ser743Pro]). Patient 2 carries the missense mutations c.1874G>A [p.His684Pro] and c.2051A>C [p.Trp625*]. These changes in the LEPR gene result in both patients in a premature termination of the protein biosynthesis and a loss of LEPR function.

Disruptions in the leptin-melanocortin signalling pathway have far-reaching consequences for the regulation of hunger, satiety, and body weight [4, 9]. The hormone leptin is secreted by the adipose tissue and reflects the energy stores of the body. Leptin crosses the blood-brain barrier and activates LEPR in the hypothalamus, initiating a complex signalling cascade. Consequently, leptin inhibits the production of the neuropeptide Y and agouti-related peptide in orexigenic neurons, while stimulating the proopiomelanocortin (POMC) synthesis in anorexigenic POMC neurons. POMC is then processed via prohormone convertase 1 into the α-melanocyte-stimulating hormone (α-MSH), which activates the melanocortin 4 receptor (MC4R). This finally mediates a feeling of satiety, reduces food intake, and enhances energy expenditure [10‐12]. In summary, the disease-causing variants in the LEPR gene found in the two patients interrupt the leptin-melanocortin signalling pathway and lead to severe early-onset obesity, pronounced hyperphagia, and permanent food-seeking behaviour.

The finding of the causative molecular diagnosis meant a great relief to the patients and their families. However, so far, there is no standardised causal treatment option for patients with disease-causing variants in the LEPR gene. Both patients could not achieve weight control by a balanced, calorie-reduced diet with increased physical activity. Recently, a first causal pharmacological treatment has been described [8] and is currently being evaluated in the phase III trial RM-493-015 and the extension trial RM-493-022. Both patients were enrolled in these clinical studies and started the treatment with the new MC4R agonist setmelanotide. Setmelanotide affects the leptin-melanocortin signalling pathway and thus the regulation of hunger and satiety by substituting the missing endogenous α-MSH. It activates the MC4R and induces a feeling of satiety, reduces food intake, and finally leads to a significant weight reduction in patients with LEPR deficiency [8].